Involvement of a receptor tyrosine kinase in the activation of cAMP and ERK1/2 by a retroviral-derived immunosuppressive peptide (98.13)

Abstract Several endogenous and exogenous retroviruses contain an evolutionarily conserved amino acid sequence (putative immunosuppressive domain, ISD) within the ectodomain of their transmembrane envelope proteins. We investigated the physiological and pathological role of ISD using a synthetic biopeptide composed of 17 amino acid CKS-17 homologous to the highly conserved region and showed that it not only exhibited important immune-regulatory functions, but also inhibited the production of IL-2, IL-12, IFN-γ, and TNF-α, while enhancing IL-10. Moreover, CKS-17 activated several intracellular signaling molecules including elevation of cAMP levels and phosphorylation of ERK1/2. Since the activation of the cAMP and ERK1/2 pathways has been shown to favor the development of Th2-type immune responses as well as influence viral replication and infectivity, these findings provided an important molecular mechanism(s) responsible for the observed cytokine patterns and virus-associated pathogenesis. In the present study, we show that AG879 (an inhibitor to TrkA, ErbB2, and FLK-1) completely blocks CKS-17-induced elevation of cAMP levels and phosphorylation of ERK1/2 using a monocytic cell line THP-1. By contrast, other receptor tyrosine kinase inhibitors (AG825, AG1296, AG1478) do not have this effect. We also show that while PI3K inhibitors (wortmannin, Ly294002) reduce the activation of ERK1/2 by CKS-17, these inhibitors have no effect on the elevation of cAMP levels by CKS-17. These results suggest that the action of the ISD may be mediated by an AG879-sensitive receptor tyrosine kinase that induces the phosphorylation of ERK1/2 through, at least, PI3K but elevates cAMP levels independently of PI3K. Supported in part by the Eleanor Naylor Dana Charitable Trust.